Submissions for variant NM_000304.4(PMP22):c.469C>T (p.Arg157Trp) (rs28936682)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Clinical Services Laboratory,Illumina	RCV000778488	SCV000914750	uncertain significance	PMP22-Related Disorders	2017-12-19	criteria provided, single submitter	clinical testing	The PMP22 c.469C>T (p.Arg157Trp) variant has been reported in two studies and is found in a total of four individuals, including three in a homozygous state and one in a heterozygous state (Parman et al. 1999; Brown et al. 2014). Parman et al. (1999) reported the p.Arg157Trp variant in a homozygous state in three siblings with a clinical diagnosis of Dejerine-Sottas disease, which is a historical name used to describe a severe and early childhood onset type of Charcot-Marie-Tooth disease (CMT). Their unaffected parents were reported to be first cousins and were both found to carry the p.Arg157Trp variant in a heterozygous state. Brown et al. (2014) identified the p.Arg157Trp variant in a heterozygous state in one individual who was referred for testing for hereditary neuropathy with liability to pressure palsies. The p.Arg157Trp variant was absent from 50 controls (Parman et al. 1999). It is reported at a frequency of 0.000015 in the European (non-Finnish) population of the Exome Aggregation Consortium, but this is based on one allele so the variant is presumed to be rare. Liu et al. (2014) studied the effect of the p.Arg157Trp variant and found an increase in formation of medium-sized aggregates, an increase in intracellular accumulation, a reduction of calnexin colocalization, and a low level of surface expression compared to wild type. Based on the evidence, the p.Arg157Trp variant is classified as a variant of unknown significance but suspicious for pathogenicity for PMP22-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Molecular Genetics Laboratory,London Health Sciences Centre	RCV001173916	SCV001337034	likely pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Invitae	RCV001229968	SCV001402432	uncertain significance	Charcot-Marie-Tooth disease, type I	2019-07-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 157 of the PMP22 protein (p.Arg157Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs28936682, ExAC 0.002%). This variant has been observed to segregate with autosomal recessive Dejerine-Sottas disease in a family (PMID: 10211478). ClinVar contains an entry for this variant (Variation ID: 8444). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
OMIM	RCV000008957	SCV000029169	pathogenic	Autosomal recessive Dejerine-Sottas syndrome	1999-04-01	no assertion criteria provided	literature only
GeneReviews	RCV000193053	SCV000243949	pathogenic	Charcot-Marie-Tooth disease and deafness	2014-12-18	no assertion criteria provided	literature only